Alzheimer’s experts are heavily divided on the causes and treatments of the disease. Some experts have recently begun doubting the treatment of amyloid buildup for patients with Alzheimer’s disease, according to recent reports.
Amyloids and Alzheimer’s Disease Treatment
A new drug for Alzheimer’s disease, aducanumab (in addition to several other drugs), targets and dissolves clumps of a protein in the brain known as beta-amyloid. This protein collects between neurons and comes in several different molecular forms. The beta-amyloid protein derives from the breakdown of amyloid precursor protein(APP), which is a larger protein that is broken down by gamma-secretase and beta-secretase enzymes in the human brain. For a long time, we have believed that in Alzheimer’s patients, heightened levels of this naturally-occurring protein accumulate – and then clump together to form plaques between neurons, disrupting cell function and leading to brain degeneration and cell death. This is partly why scientists became suspicious that beta-amyloid was the culprit. Furthermore, patients with a specific form of Alzheimer’s have genetic mutations that are linked with difficulty getting rid of beta-amyloid.
Drug trials for aducanumab were halted in early 2019 by Biogen, a global biotechnology company, as skepticism began to arise among experts regarding whether the compound was actually improving memory in Alzheimer’s patients who were experiencing cognitive decline. Several months later into 2019, Biogen and its Japanese partner drug maker, Eisai, stated that they would request approval for the drug from the U.S. Food and Drug Administration. According to Biogen, a new analysis showed that a significant number of patients undergoing high doses of the drug benefited from the compound.
Divisions Among Experts
Despite the new findings and the fact that many experts continue to support the amyloid hypothesis,, numerous others continue to scratch their heads regarding the treatment of amyloid, which is the leading target for dementia treatment today. From the myriad of drug failures to the inability of many other compounds aimed to reduce amyloids, experts remain divided about whether treating amyloid buildup is the best approach for Alzheimer’s treatment.
For example, John Jardy, who runs a molecular neuroscience program at University College London’s Institute of Neurology and helped to generate the initial amyloid hypothesis over two decades ago, is now rethinking the theory. He states that when the concept was drawn up in 1998, there were many questions to be answered – many of which remain unanswered. He also believes that although the hypothesis has strong data to support it, that amyloid-targeted drugs might not be as effective if given too late in the progression of the disease.
Other experts believe that amyloid may be an important biomarker (not the culprit itself), helping us to better understand the disease and its risk; it can perhaps helpi us to better diagnose patients in earlier stages.
Although it doesn’t seem that the amyloid hypothesis is anywhere near its close, scientists do seem to be a bit more skeptical than they once were about it, looking more widely at other processes at this disease of cognitive degeneration.
Furthermore, in addition to the numerous amyloid-targeted drug failures, more reason for skepticism remains due to mismatches between amyloid levels and dementia. Changes in brain function, including the development of beta-amyloids, often begin years before the cognitive impairment associated with Alzheimer’s Disease. Also not every patient who has high levels of amyloids develops the disease. Thus, amyloid may be the culprit for some patients and a bystander or a biomarker for others.
New research suggests that the buildup of the amyloid protein is only a part of many interactions that occur in patients with dementia. Dr. Howard Feldman, director of the Alzheimer’s Disease Cooperative Study, asserts that it is not likely that a single amyloid intervention will “stem the tide of the disease.” Amyloid buildup might help to explain the early-onset, genetically driven forms of Alzheimer’s, but for late-onset forms of the disease, there may be multiple problems – and amyloid is not one of them.
Other experts believe other proteins may account for dementia in late-life. For example, Karen Duff of Columbia University believe that the tau protein tangles play an essential part that is more important than beta-amyloid. Other scientists believe that defects in the blood-brain barrier or inflammation play a larger role. Yet, just as is the case with beta-amyloid targeted drugs, drugs that target tau and inflammation are not yet proven to be effective.
For patients with late-onset Alzheimer’s and other neurodegenerative diseases, a faulty immune response may be to blame, according to Hardy and his colleagues. They theorize that with the early accumulation of beta-amyloid, neural cell membranes might be damaged. If microglia immune cells are unable to remove the damaged membranes, it might also prevent the clearing of more amyloid, leading to a cycle of damage. Many risk factor genes associated with late-onset Alzheimer’s are linked with microglial metabolism.
Yet some scientists still remain convinced that amyloid has a significant role due to many studies that had provided a link to Alzheimer’s disease. David Holtzman, chair of neurology at Washington University School of Medicine in St. Louis, has no question that beta-amyloid is important in the treatment of the disease. He also believes that amyloid levels may rise in patients with insomnia, which provides a link between lifestyle habits, amyloid, and Alzheimer’s disease.
What we do know at this point is that Alzheimer’s is debilitating, which is why experts continue to push forward in determining what exactly causes the disease. Hopefully someday the answer to this question will be wholly known, but until then, experts continue to aggressively research the cause of this cruel neurological disease. The best recommendation they have, as outlined in three books by Dr. Majid Fotuhi, is to exercise more, sleep better, reduce your stress, and be keep your mind challenged.
To learn more about how you can improve your memory and assess your current level of brain function (and risk for developing Alzheimer’s disease), please visit us at www.neurogrow.com
This blog was written by Ms. Courtney Cosby, and edited by Dr. Majid Fotuhi.